The treatment of cancer has thus far proved problematic. While “cancers” share many characteristics in common, each particular cancer has its own specific characteristics. Genetics and environmental factors have a complex interplay in severity and prognosis of treatment. Thus, treatment must be carefully tailored.
Certain pharmaceutical treatments have proved useful for one form of cancer, but not others (Hollad and Frei, et al, Cancer Medicine, 4th ed. Publisher Williams & Wilkens). Other treatments such as radiation, while partially useful for a range of cancers, do not typically result in a complete cure. Indeed, given the severity of many cancers and the mortality rate, a drug can be deemed successful if it improves quality of life, e.g., by delaying growth of tumors, or prolongs life—without actually curing the condition. Thus, in many circumstances, an individual is treated with a compound or combination of treatments that can eliminate 90-95% of the malignant cells, but the remaining cells can regrow and metastasize, ultimately resulting in death. Among cancers with particularly poor ultimate prognoses is ovarian cancer.
Combination therapies, while desirable, are a hit or miss proposition. The treatments are typically not additive. In many cases, cross effects and treatment load can result in lower effectiveness for the combinations, than either treatment alone. Problems encountered include multiple drug resistance (MDR), where the malignant cell in essence pumps the cytotoxic compounds and other compounds out of the cell, thereby preventing continued useful treatment of the cancer.
There are a number of cytotoxic agents that are currently being used or studied for the treatment of cancer. One of these, Paclitaxel, (also referred to as TAXOL®) was first identified in 1971 by Wani and collaborators (Wani M C et al., 1971 J. Am. Chem. Soc., 93: 2325-2327) following a screening program of plant extracts of the National Cancer Institute. This complex diterpene shows cytotoxic activity against several types of tumors and is presently used in the treatment of some cancers such as ovarian and breast cancers. Clinical studies suggest that TAXOL® could eventually be used in the treatment of over 70% of human cancers.
Paclitaxel differs from other cytotoxic drugs by its unique mechanism of action. It interferes with cell division by manipulating the molecular regulation of the cell cycle. Paclitaxel binds to tubulin, the major structural component of microtubules that are present in all eukaryotic cells. Unlike other antimitotic agents such as vinca alkaloids and colcichine, which inhibit the polymerization of tubulin, paclitaxel promotes this assembly of tubulin and stabilizes the resulting microtubules. This event leads to the interruption of cell division, and ultimately to cell death.
The antitumor property of taxoid compounds has also lead to the generation of new anticancer drugs derived from taxanes. Taxotere™ (sold by Rhône-Poulenc Rorer), which is produced from 10-deacetylbaccatin III by hemisynthesis, is currently used in the treatment of ovarian and breast cancers.
While agents such as TAXOL® and Taxotere have made an advance in the treatment of metastatic ovarian and metastatic breast cancer, the majority of those treated still ultimately succumb to these diseases.
β-lapachone, a quinone, is derived from lapachol (a naphthoquinone) which can be isolated from the lapacho tree (Tabebuia avellanedae), a member of the catalpa family (Bignoniaceae). Like camptothecin and topotecan, β-lapachone inhibits DNA Topoisomerase I (Li, C. J., et al., J. Biol. Chem., 1993). This compound has been found to be effective against several types of cancer cells in vitro, including lung, breast, colon and prostate cancers and malignant melanoma (Li, C. J., et al., Cancer Research 55:3712-3715 (1995) and unpublished data).
β-lapachone works by disrupting DNA replication. Topoisomerase I is an enzyme that unwinds the DNA that makes up the chromosomes. The chromosomes must be unwound in order for the cell to use the genetic information to synthesize proteins; β-lapachone keeps the chromosomes wound tight, and so the cell can't make proteins. As a result, the cell stops growing. Because cancer cells are constantly replicating and circumvent many mechanisms that restrict replication, as is the case with normal cells, they are more vulnerable to topoisomerase inhibition than are normal cells. However, treatment with these compounds is also only partially successful—inhibiting and delaying growth of the malignant cells.
No single drug or drug combination is curative for advanced metastatic cancer and patients typically succumb to the cancers in several years. Thus, new drugs or combinations that can prolong onset of life-threatening tumors and/or improve quality of life by further reducing tumor-load are very important.